Ezetimibe Induces Vasodilation in Rat Mesenteric Resistance Arteries through Inhibition of Extracellular Ca2+ Influx

Figures

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  Figure 1. Ezetimibe-induced vasodilation in rat mesenteric arteries. (A) Data showing responses to vehicle (DMSO, 0.008–0.081%). (B) Representative trace demonstrating responses to cumulative administration of ezetimibe (5–50 µM) on U46619 (500 nM)-induced vasocontraction. (C) Statistical analysis of the relaxation response to U46619. Data are shown as mean ± SD (n = 5). W/O: wash out. *** p < 0.001, **** p < 0.0001.

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  Figure 2. Endothelium-independent relaxation induced by ezetimibe in mesenteric arteries. Typical trace showing ezetimibe-induced relaxation in the endothelium-intact (A) and endothelium-denuded (B) mesenteric arteries. Statistical analysis of ezetimibe-induced vascular relaxation (C), and the vascular relaxation in response to ezetimibe in the presence of eNOS inhibitor L-NNA (300 µM, (D)). Mean ± SD (n = 5). ACh: acetylcholine; L-NNA: Nω-Nitro-L-arginine; W/O: wash out.

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  Figure 3. Effect of K+ channel blocker TEA (tetraethylammonium) on ezetimibe-induced vascular relaxation. Effects of ezetimibe on the pre-contracted arteries with U46619 (500 nM) in the presence (A) and absence (B) of TEA. (C) Statistical analysis of the relaxation response of ezetimibe in the presence of TEA. Vasodilation of arteries is expressed as the percentage of the contraction induced by U46619 (500 nM). Mean ± SD (n = 5). W/O: wash out.

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  Figure 4. Ezetimibe inhibited vasocontraction induced by extracellular Ca2+. Representative traces showing the contraction responses by repeated addition of CaCl2 (0.1–2.0 mM) in the absence of ezetimibe (A) and in the presence (B) of ezetimibe (30 µM). (C) Statistical analysis of contraction induced by CaCl2 in the mesenteric arteries with or without ezetimibe. Mean ± SD (n = 5). W/O: wash out; CPA: cyclopiazonic acid. *** p < 0.001, **** p < 0.0001.

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  Figure 5. Ezetimibe reduced contraction induced by L-type voltage-gated calcium channel activation. Representative traces showing the effects of the vehicle (DMSO, (A)) and ezetimibe (B) on BAY K 8644-induced contraction. (C) Statistical analysis of relaxation induced by ezetimibe in the mesenteric arteries pre-constricted by BAY K 8644. Mean ± SD (n = 5). W/O: wash out. ** p < 0.01, **** p < 0.0001.

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  Figure 6. Ezetimibe decreased the phosphorylation of MLC20. (A) Representative western blot analysis of phosphorylated MLC20 (P-MLC20) and total MLC20 (T-MLC20) in control VSMCs, VSMCs treated with U46619 (500 nM), and VSMCs co-treated with U46619 (500 nM) and ezetimibe (30 µM). (B) Quantitative data for phosphorylated MLC20 (n = 5). ** p < 0.01, *** p < 0.001.

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  Figure 7. Graphical illustration of ezetimibe-induced vasodilation. MLC20: 20 kDa myosin light chain; MLCK: myosin light-chain kinase; MLCP: myosin light-chain phosphatase.